For a long time, tumor is one of the major causes of death in the world. Although there have been relatively mature therapies, many types of tumors lack early symptoms and are not sensitive to radiotherapy and chemotherapy. Many chemotherapeutic agents can damage the immune system in organisms, have toxic and side effects in patients, and result in drug resistance. Especially, when tumor develops to a middle and advanced stage, the speed of treating tumor is generally much slower than the speed of tumor metastasis and spread. Therefore, anti-tumor treatment has always been faced with severe challenges. In order to achieve a better therapeutic effect of tumor, there is a strong demand for novel effective anti-tumor agents and combination therapy strategy.
Antiangiogenesis is regarded as one of the strategies having significant medical value for the treatment of malignant tumor. When tumor volume exceeds 2 mm3, the tumor is in the vascular stage, and the formation of new blood vessels provides the necessary nutritional supply and metabolic excretion for the growth of tumor, resulting in exponential increase in tumor volume. At the same time, since new blood vessels has enhanced permeability, tumor cells can penetrate the blood vessels and migrate to other parts. Therefore, angiogenesis is closely associated with tumor growth, metastasis and recurrence. Blocking tumor angiogenesis and breaking the nutritional supply of tumor tissue have become a new target for anti-tumor therapy, and have also become a hotspot in researches on anti-tumor therapy. The emergence of angiogenesis inhibitors provides a new way for anti-tumor therapy. However, with the enlargement of clinical application and the extension of application time, angiogenesis inhibitors gradually exhibit some side effects. Bevacizumab (Avastin), the first approved drug for inhibiting tumor angiogenesis in the United States, can bind to vascular endothelial growth factor (VEGF) and blocks its biological activity, and is widely applied in clinical treatment now. However, its effect is not satisfactory as it has a lot of serious side effects. Studies show that cancer metastasis is resulted from the co-modulation of multiple growth factors. Therefore, the problem may be solved by the development of novel angiogenesis inhibitors capable of inhibiting multiple growth factors simultaneously.
Matrix metalloproteinases (MMP), a family of zinc-dependent endogenous proteases, have been shown to play an important role in tumour invasion and metastasis and angiogenesis due to their ability to hydrolysis the extracellular matrix. Tumour metastasis is also accompanied by the hydrolysis of extracellular matrix with protease. Therefore, downregulating MMP expression or decreasing MMP protease activity in cell microenvironment is crucial for inhibiting angiogenesis, and preventing tumour invasion and metastasis. Inhibitors targeting to MMP-2 and MMP-9 have been widely applied in tumour-metastasis animal model and been studied in human cancer in clinic. For example, Fe3O4 nanoparticles coated with piroctone olamine (PO), i.e., Fe3O4@PO NPs, have the activity of inhibiting MMP-2. The fullerene-based nanoparticle Gd@C82(OH)22 and hollow mesoporous carbon nanocapsules (HMCNs), as potent antiangiogenesis inhibitors, can down-regulate the activity of multiple angiogenic factors including MMP-2 and MMP-9.
Iron is a crucial microelement in organisms. Iron-based complex are effective cytotoxic drugs. Iron-based active compounds are different from the currently used platinum-based drugs in terms of mechanism of action, biological distribution and cytotoxicity, and are effective, or at least substantially effective against cancer that is poorly sensitive to chemotherapy or is resistant to traditional platinum-based drugs. However, there is still no report on the use of iron-based complex as an anti-tumor drug targeting to angiogenesis.
Metal-organic frameworks (MOFs) are a class of porous crystalline materials with periodic multidimensional network structure, formed by self-assembly of metal ions and organic ligands. In recent years, since MOFs have tunable pores and extremely high surface areas, they can be widely applied in multiple fields such as biomedicine, such as encapsulation, delivery, transport and release of drugs, and MOFs can even be used to achieve the gene therapy of disease. Studies have shown that silencing VEGF expression via RNA interference can inhibit tumor angiogenesis and block tumor growth. Therefore, Fe-containing metal-organic frameworks can be used to prepare novel anti-tumor angiogenesis inhibitors, in order to achieve the effect of anti-tumor therapy. Now, there is no report on the inhibition of MMPs or anti-angiogenesis by MOFs materials themselves.